Iron loading increases cholesterol accumulation and macrophage scavenger receptor I expression in THP-1 mononuclear phagocytes

Epidemiological studies have established that a high level of iron body stores is associated with increased risk of acute coronary heart disease. To explain this association, it has been proposed that iron catalyzes the production of highly reactive forms of free oxygen species, and thus, promotes low-density lipoprotein (LDL) oxidation, a lipoprotein that plays a critical role in atherogenesis. However, few studies have provided evidence to support this hypothesis. In the present study, we determined the effect of iron loading of THP-1 mononuclear phagocytes on LDL metabolism. We demonstrated that iron loading of THP-1 cells stimulated conjugated diene formation in LDL in the culture medium. In addition, iron loading of THP-1 cells significantly increased cholesteryl ester accumulation in cells exposed to native LDL, suggesting that during the incubation of the cells with native LDL, the LDL became oxidized and was taken up by the cells. We further demonstrated that the degradation of 125I-oxidized LDL was significantly increased in iron-loaded THP-1 cells. Lastly, we demonstrated that iron loading of THP-1 cells stimulated scavenger receptor expression in these cells. In conclusion, this study demonstrates that loading of mononuclear phagocytes with iron leads to oxidization of LDL, increased cellular cholesterol accumulation and scavenger receptor expression, and supports the hypothesis that increased macrophage iron levels promote atherogenesis.